The principal goal of this proposal is to identify a gene or genes responsible for the development of focal segmental glomerulosclerosis (FSGS) in families with autosomal dominant inheritance of this condition. The underlying hypothesis of this work is that identifying the etiology of single-gene forms of FSGS will yield considerable and novel information into the biologic pathways responsible for more common forms of FSGS, including secondary forms of FSGS, as well as glomerulosclerosis resulting from diabetes and hypertension. We have identified, clinically characterized, and collected DNA samples from a large number of families with this condition. In the largest two families, we have mapped the responsible gene to a 3.5 centimorgan region of human chromosome 19. Linkage analysis in several other families indicate that this locus does not harbor the defective gene in all families with FSGS. We intend to refine the location of the FSGS gene at this chromosome 19 locus by identification of additional recombination events. Towards this goal we will expand the families under study and continue to collect additional families. We will build a BAC contig to complement the exist physical and genetic map of the chromosome 19q13 region in order to map ESTs, STSs, microsatellites, and genes within this interval. We will then identify the FSGS gene by a combination of gene identification methods and sequence analysis. We will next examine this gene in other small families with FSGS and individuals with primary and secondary FSGS. Identification of a gene responsible for renal dysfunction in these families will identify a novel biologic pathway in the development of focal segmental glomerulosclerosis. These studies will identify the gene for a previously unrecognized cause of renal failure, provide insight into the biology of glomerulosclerosis, and identify a biologic and genetic pathway which may be responsible for a significant proportion of renal dysfunction in the general population.